Cervical cancer is the second most common cause of cancer death in developing nations, with about 370,000 new cases annually having a 50% mortality rate. In the past five decades, there has been a 75% decrease in incidence and mortality from cervical cancer in developed nations. Most of this decrease is attributed to the effective institution of cervical cancer screening programs, including regular Pap tests. There are several known risk factors for cervical cancer. An important risk factor for cervical cancer is the infection with a virus called HPV (human papillomavirus). HPV infection is a necessary factor in the development of nearly 70% of cases of cervical cancer. Because the underlying causes for cervical cancer are complex, identifying a reliable biomarker for this deadly disease has been elusive.
Early diagnosis for cervical cancer and prompt treatment cure nearly all cases of cervical dysplasia and neoplasia. The five year survival rate for patients with stage I cervical cancer is 80% or more. The five year survival rate drops to about 60% for patients with stage II cervical cancer and then drops to about 32% and 15% for those with stage III and stage IV cervical cancer, respectively. In order to ensure that cervical cancer is detected early, repeated Pap tests are recommended. However, cervical cytology is expensive, and requires Board-certified pathologists to review one by one and interpret the results from Pap smears.
There are several reports regarding different purported biomarkers for cervical cancer. U.S. Pat. No. 7,157,233 discloses many cell cycle regulation genes (i.e., S-phase genes) including p14ARF, p21waf1, Topo2A, and cyclin E as potential biomarkers for cervical dysplasia and neoplasia. U.S. Pat. No. 7,045,292 discloses an association between increased c-myc and cyclin D2 and Chronic Lymphocytic Leukemia. U.S. Pat. No. 7,186,514 discloses a new gene (i.e., MN gene) present in the chromosomal DNA that may have potential implications in tumorigenicity in many tissues, such as cervical tissue. U.S. Patent No. 2005/0186215 discloses the identification of a novel human gene (i.e., CUDR) as a biomarker in human cancer. All of these studies have not utilized sufficient clinical tissues from cervical cancer patients, and there is a lack of clinical validation. Furthermore, these genes represent unique cell cycling key regulators shared by many normal and tumor cells (i.e., not unique for cervical cancer).
U.S. Pat. No. 6,709,832 discloses another cell cycle regulatory protein (i.e., p16INK4a). Using paraffin sections, these authors discovered that p16INK4a is over-expressed in cervical biopsies of dysplastic cells (i.e., CIN I, II and III) as well as in invasive carcinomas. The over-expression of p16INK4a seems to increase with the degree of dysplasia towards the invasive carcinoma. It can take 10 years or longer for cervical dysplasia to develop into cervical cancer. Because p16INK4a peaks at around CIN III (i.e., precancerous stage) (See, Table 2 of '832 patent) and that not all CIN III females will progress into invasive carcinoma (i.e., cancerous stage), it suggests additional factor(s) other than p16INK4a may contribute to the progression of cervical cancer. The role of p16INK4a as biomarker requires further clinical validation. U.S. Pat. No. 7,306,926 further discloses a method of using a solubilized cervical sample to measure p16INK4a and determining the elevated levels as a means of diagnosis and detection of cervical cancer. The commercial utility of this technology remains to be validated. To date, p16INK4a is the only commercially available biomarker for cervical cancer.
Accordingly, there exists a critical and continuing need to identify novel molecular biomarkers and develop them into clinical diagnostic assays for cervical cancer detection. There exists also a demand for a reliable biomarker that has high sensitivity and specificity. The present invention cures all the prior art deficiencies and provides a method of using CIP2A as a biomarker and its combined usage with additional biomarkers for the detection and diagnosis of cervical cancer. The present assay provides a high sensitivity and specificity of over 90%.